New compounds interfering with regulators of epigenetics profiles

The first epigenetic targeting drugs (DNMT and HDAC inhibitors) have efficacy in some types of cancer but are limited by either target related or side effect toxicity. The full potential of epigenetic based therapies has not yet been fully realised due both to the limitations of biological knowledge on specific targets and to defective strategies in current drug discovery approaches based on recombinant, single target assays. Although deregulated expression of a few epi-targets has been found in cancer, functional results are required to determine which of them would qualify as candidate drug targets. Thus, BLUEPRINT utilises novel RNAi screens to validate epigenetic targets in ex vivo and in vivo settings. Particularly relevant is the concept of direct in vivo validation of candidate epigenetic targets, an approach that has not been tried before on a selected set of candidate drug targets. We will perform immediately the in vivo RNAi based screens in murine leukaemia models and patient derived human samples, in order to achieve the most relevant level of preclinical validation possible. Cell assays and screens will be a complement to the in vivo screens, and will be used for further validation, and -most importantly- for further characterization of the biological phenotypes, and to provide assays for the drug discovery process. Thus, the conventional process of gradual validation (from in vitro to in vivo studies) will be subverted, and an innovative strategy will be aggressively pursued.
BLUEPRINT will pioneer approaches to drug discovery based on isolating epigenetic complexes directly from human cells or tissues, thus preserving their native multi-component structure. This is an essential requirement for focused target identification and compound optimisation to produce clinically relevant therapeutics. For instance, the Episphere approach by SME partner Cellzome has already identified novel HDAC/protein complexes specific for defined cell states and several novel targets for HDAC inhibitors have been discovered. By screening existing, non-HDAC inhibitors for binding to HDAC complexes, potential new uses for these drugs as epigenetic modulators have been discovered, allowing either direct application as epigenetic therapies or as novel starting points for new lead optimisation on HDAC targets. Additionally, Episphere has revealed new, unexpected selectivity of known HDAC clinical stage inhibitors and lack of activity against specific HDAC protein complexes. We believe many of these basic principles can be extended to other epigenetic target classes.

Research Area Leader: Gerard Drewes
Identification and validation of Epi-targets Leader: Lucia Altucci
Compound development and screening Leader: Gerard Drewes